Substituted succinimides



Patented June 23, 1953 UNITED STATES PATENT OFFICE SUBSTITUTED SUCCINIMIDES Charles A. Miller, Detroit, and Loren M. Long, Grosse Pointe Woods, Mich, assignors to Parke, Davis & Company, Detroit, Mich, a corporation of Michigan No Drawing. Application April 12, 1950, Serial No. 155,562

4 Claims. (01. 260-3265) This invention relates to two new substituted succinimides which possess a remarkably high order of a particularly valuable type of anticonvulsant activity. More particularly, the invention relates to succinimides represented by the formula,

in which R3 has the significance given above.

The products of the invention are particularly useful in the treatment of the petit mal type of epileptic seizures. They are unique in that they are highly effective against this type of convulsion without the production of the undesirable hynotic effects usually associated with other anticonvulsants. The products are also of value in the treatment of the grand mal type of epileptic seizures.

When tested by the standard electro-shock methods of Putnam et al. (Science, 85, 525 (1937)) utilizing cats and that of Toman et al. (J. Neurophysiol, 9, 231 (1946)) utilizing mice, the products of the invention exhibit a high degree of anticonvulsant activity as shown in the table. As will also be seen from the table the products of the invention show a high degree of activity in the so-called anti-metrazol test for the petit mal type of convulsion. This test is performed by feeding five rats weighing 150- 200 g. each a predetermined quantity of the drug to be tested, followed in one-half hour by the subcutaneous injection of 93 mg./kg. (95-100% of the convulsive dose) of metrazol (pentame-thylene tetrazole). The rating of the drug is based on the number of the five rats which are protected from convulsions within the half hour following the injection of the metrazol, a 4+ rating indicating the protection of all five animals.

TABLE RlC -CH2 O= G=0 CH:

Electra-shock, Electra-shock .Anti-Metrazol Cat Test Mouse Test- Test Dose of Drug R8 (mg/kg.) which Dose protects 50% of Dose Rating Level, i g g f? Rating Level, -I l s-I e- CrHi ca. 100 4+ 33 1+ 16 CH; 1+ 100 ca. 120 4+ 3+ 33 1+ 16 These compounds are quite non-toxic. For

example, for N-methyl-a,a-methylphenylsuccinimide, the M. T. D. is 900 mg./kg. and the LD5o is 1550 men/kg. for single massive doses perorally in mice. No cumulative toxic effect in mice and dogs is noticed. a-Ethyl-N-methyl-a-plhenylsuccinimide produces moderate depression at 500 mg./kg. In general, these compounds are nontoxic, produce no cumulative toxic efiect and have no toxic effect on the hematologic system.

The invention is illustrated by the following examples:

I Example 1 10 g. of a-phenyl-a-ethylsuccinic acid and 10 g. of 40% aqueous methyl amine are heated together at ZOO-250 C. until no more disillate is obtained. The resulting residue is then vacuum distilled. The N-methyl-a-phenyl-a-ethylsuccinimide, which has a boiling point of 122123 C. at 0.1 mm. has the following structure I OH;

Example 2 g. of e-phenol-a-methylsuccinic acid and g. of 40% aqueous methyl amine are heated together at 200-250 C. until no more distillate is obtained. Upon vacuum distillation of the residue, the N-methyl-a-phenyl-a-methylsuccinimide, of boiling point l21-122 C. at 0.1 mm. is

obtained. After recrystallization from aqueous 2. N-methyl-a-phenyl-m-ethylsuccinimide. ethanol, this compound melts at 52-53 C. and 3. N-methyl-a-phenyl-a-methylsuccinimide. has the formula 4. A therapeutic agent consisting of a com- CH3 position in dosage unit form comprising N- O 1 CH 5 methyl-a-phenyl-a-ethylsuccinimide in non toxic amount effective against ep p c o vul- 0=0 o=0 sions.

\/ .t v CHARLES A. MILLER.

I LOREN M. LONG. CH: v 10 Attention is directed to a copending applica- References Cited in the file of this patent tion September 26, Serial NO. which is in part a continuation of the instant application and which discloses related chem- Number Country Date ical compounds useful in the treatment'of the 5 389,943 Germany 1, 1922- petit mal type of epileptic seizures.

What we claim is: 1. A compound of the formula CsHs Ri-C---CHa Y 5 1 wherein R3 is loweralkyl. 

1. A COMPOUND OF THE FORMULA 